Dr. Shaji Kumar of the Mayo Clinic discusses the road to personalized myeloma treatment and three approaches we can take today before targeted treatments become a clinic reality

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Originally posted on mPatient Myeloma Radio

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Dr. Shaji Kumar, MD Mayo Clinic Rochester

Interview date: September 27, 2013

Summary

Dr. Shaji Kumar, MD discusses the unique opportunity we have with myeloma compared to other cancers where we can detect and potentially treat early if  we can determine when and for whom early intervention (like MGUS and smoldering) is effective. He shares how we are getting closer to personalized myeloma treatment and how we can better target high-risk myeloma patients. Until we get to that type of targeted therapy, he shares the three approaches to improve care for active myeloma at the Mayo Clinic. First, better drugs with added advantages like ixazomib, an oral version of Velcade. Second, totally new classes of drugs like the monoclonal antibody, elotuzumab , a new way to stop myeloma cell division (ARRY-520), and new drugs like dinaciclib that work on the CD38 pathway to shut down myeloma’s ability to communicate and replicate. Third, he describes how combinations of current therapies are being used to improve care. Finally, he shares if a large number of myeloma patients were to have their genome sequenced and reviewed in a trial, we could find and determine specific genetic mutation targets for new therapies. 

 

The live mPatient Radio podcast with Dr. Kumar

Full Transcript
Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. The goal of this series is to help you understand that your participation in clinical trials matters greatly. The doctors and researchers are setting the targets, but we are the ones who are helping them get there faster.

We encourage you to sign up for mPatient minute newsletter where we post our upcoming show and past interview in a weekly email. You can do this on our homepage, www.mpatient.org. You can find links to our Twitter and Facebook pages on the homepage as well.

So I am excited to have a conversation today with Dr. Shaji Kumar of the Mayo Clinic in Rochester. Welcome, Dr. Kumar.

Dr. Kumar: Thank you.

Jenny: Thank you so much for joining us. Now before we start, I like to give everyone a short introduction for you.

Dr. Kumar is a professor of medicine at the Mayo Clinic in Rochester and is a consultant in the Division of Hematology Internal Medicine at the Mayo Clinic. Dr. Kumar studied medicine in India, the top All-India Institute of Medical Sciences. He performed his residency and fellowship with the Mayo Clinic and was a research associate at Dana-Farber. He is a Mayo Foundation Scholar in multiple myeloma. He is a member of the AMA, ASH/ASCO, the American Association for Cancer Research and Society for Clinic Trials.

He is an editor and board member for numerous journals including Advances in Hematology, the American Journal of Hematology, Leukemia, and the European Journal of Clinical and Medical Oncology. He is a Principal Investigator on a very large number of trials at the Mayo Clinic, and he helps to construct and coordinate many of their trials.

So thank you much for joining us today.

Dr. Kumar: Thank you, Jenny. Good evening, everyone, and thank you for joining today. What I would like to do is go over the landscape of what myeloma is today and the related diseases and the dramatic changes that have happened in terms of both treatment as well as other supportive care for this disease that have resulted in patients living a lot longer than what used to be short of ten years ago.

When we talk about multiple myeloma, it is really the tip of the iceberg. We are really talking about a large group of diseases what we call monoclonal gammopathies. The vast majority of the patients who have a myeloma protein or an M protein or a monoclonal protein — I’m sure you all have heard that terminology — have what we call a monoclonal gammopathy of undetermined significance. Now, this is something that increases as patients get older. If you were to take a hundred 70-year-old people, about six out of 100 would have a monoclonal protein or M protein in their bloodstream.

Now, the vast majority of these patients who live a normal life span may die of something totally unrelated, but only about 20% of people diagnosed with this monoclonal gammopathy of undetermined significance will get to a stage where the monoclonal protein or the increased numbers of plasma cells in their bone marrow would require any kind of therapy or intervention. We don’t know what causes people to get this abnormality, but the culprit is the cell that we call a plasma cell. The plasma cells are cells of the immune system that you all have, which basically make proteins or immunoglobulins to try and fight infections and so forth.

Now, for some reason which we don’t fully understand, these cells become abnormal and they increase in numbers and after a point, they start affecting the other cells in the bone marrow as well. These abnormal cells also create a lot of proteins what we call as the monoclonal protein, and this protein by itself can also create problems by causing renal failure, for example, by plugging up the kidney tubule. These cells also can secrete a lot of chemicals which can result in the bones getting weaker. That is why patients with myeloma will often depend on those four features to make a diagnosis of active myeloma namely the bone disease, kidney problems, the anemia that it can cause, as well as the increased levels of calcium that can sometimes be seen in these patients.

But as I said, the vast majority of the people have this monoclonal gammopathy of undetermined significance which does not need any intervention but do need very careful monitoring over time because it’s not always easy to predict who among these patients will go on to develop multiple myeloma. A lot of research has been done and is currently ongoing trying to understand what actually is responsible for the conversion from this MGUS relatively benign stage to a malignant multiple myeloma stage. We think it’s a combination of things that happens with these plasma cells as well as things that happen around the plasma cells in the bone marrow in terms of increased blood vessels, in terms of decreased immune surveillance and so forth.

We also have over years categorized a phase in this illness that we call smoldering multiple myeloma which is kind of the gray zone in between the MGUS and the multiple myeloma. This phase where the — basically these myeloma cells or the numbers, but it still has not gotten to a point where it’s creating any kind of problem to the body. Again as with MGUS, patients with smoldering multiple myeloma, we just carefully watch them overtime to make sure none of those bad features we talked about is actually happening which is usually the trigger for us to start treatment.

Now, while this is something that they have to continuously year after year where we have to monitor the patients, it also gives us the opportunity actually to maybe intervene early on to see if we can actually alter the course of the disease. So maybe can we actually intervene in somebody who have MGUS and do something so that this patient will never develop myeloma or can we intervene in the smoldering phase to prevent this from becoming active multiple myeloma?

This is a very active area of research and some of you may have read reports about a recent clinical trial that came out where patients with smoldering multiple myeloma who are at the highest risk of getting active multiple myeloma were enrolled on a clinical trial and half of them were treated with Revlimid and dexamethasone, and the other half of the patients were just observed which is what we do currently. The results of the trials are quite interesting in that the patients who got the Revlimid ahead of time lived much longer than the people who did not.

Now, the way the study was done, the way they identified these patients at the highest risk of developing myeloma is not something that you routinely use today. So I think while this provides some proof of concept that maybe an early intervention has some role in this disease, we still need to do more studies to identify who are the patients who are most likely to benefit from this early intervention. Currently, there are clinical trials that are ongoing. One best example in this country is the Eastern Corporative Oncology Group trial that is available across the country who are patients that are actually being kind of randomized by the flip of a coin, half would Revlimid and the other half would get no treatment but just being observed as we do currently.

Jenny: And this is smoldering myeloma, right?

Dr. Kumar: This is smoldering myeloma. That’s right. So this trial is going to be very important because this will give us additional information. One, what we saw in the Spanish route is that proof of principle, is that being still hold through. The second thing is we are using methods to identify patients with high-risk which is something — using the third set we currently use in the clinic. So the results of this clinical trial would be — it can be implemented in the daily practice. There are other clinical trials ongoing as well looking at other mortalities in patients with smoldering myeloma if we can actually alter the natural history of this disease.

Jenny: I have a question for you because now you are talking about smoldering myeloma and I have heard other researchers talk about treating smoldering myeloma, but I’ve never heard them talking about treating potentially MGUS at an early stage.

Dr. Kumar: Right. So I think this — basically, the fact that there is this whole spectrum of disease that happens before patients get myeloma presents with an opportunity which very cancers have where we can intervene. The best example will be colon cancer. You will find polyps, you take it out and you prevent the cancer from happening. So can we replicate the same scenario in patients with monoclonal gammopathy of undetermined significance? The problem is — when you talk about MGUS. It is a very proportion of patients who actually get myeloma and that’s on a very long period of time.

So the chance of — you would have to treat a lot of patients to or a lot of people with MGUS do actually do prevent one myeloma from developing. The risk/benefit ratio is different. So they really have to have some treatment that is very non-toxic to be able to implement that in patients with MGUS. So I think that’s the critical difference between how we might intervene in MGUS versus how we might intervene in smoldering myeloma.

Jenny: Well, that would be exciting to know when you should use it and when you should not.

Dr. Kumar: Exactly. I think the key thing is to understand what are the triggers that make a MGUS go into myeloma? The second thing is when that change happens, we know it’s a slow transition, can be actually identified some markers on the plasma cells that will tell us this particular cell is already two-thirds of it towards being a real cancer so it can be maybe intervened now. But the problem is when you look under the microscope the cells in the bone marrow from a patient with MGUS and the cells in the patient from active myeloma, they don’t look very different. In the way they look unlike some of the other cancers. That is one of the biggest dilemmas that we have today as to identifying in whom should we intervene?

Jenny: I have a question about that. Could it possibly be when a certain gene gets activated rather than a change in the cell?

Dr. Kumar: Definitely something changes in the cell and we know that it’s not the appearance of the cell so it’s something within the cell that changes and we think it’s basically the chromosomes or the genitc material in these cells undergo damage, further damage over time and they keep changing to the point where it kind of gets to the tipping point and now the cell really takes off and behaves really like a cancer cell. So the underlying, the underpinnings of these change is clearly genetic within the myeloma cell. But the question is how much of this different by what happens within the myeloma cells versus what is happening in the cells around the myeloma cell? It’s not just the seed. It’s also the soil that changes with time so that patients actually go from the MGUS to myeloma. Before I can switch over to kind of what we are doing that patients with active myeloma, I just want to see if there is any question specifically with this aspect.

Jenny: Well I just think it’s an interesting study to think about the environment and what’s happening in that environment and I have been reading a little bit about that about how the environment inside of your bone marrow, makes a big difference as well like you were saying.

Dr. Kumar: Yeah, no. I think it’s a field that’s very actively being pursued not just in myeloma but in all cancers. I think increasingly they realize that it’s not just the cancer cell in isolation that is undergoing the changes, but it’s also adapting the environment around it to facilitate its own growth. I think by understanding how that happens, we can potentially make the environment less conducive for the cells to grow and thus maybe slow down the whole cancer process.

Jenny: Okay. All right. Thank you

Dr. Kumar: So moving on to active myeloma, again as I said, this is the tip of the iceberg but obviously these are the people who need the active intervention in an urgent fashion so that things don’t get any worst and we can actually get things under control. When patients have active myeloma, it typically means that these myeloma cells or the protein that’s being made by the myeloma cells or other chemicals that are being secreted by the myeloma cells actually making the bones weaker, the calcium levels can go up, the kidneys can shut down, and patients can become anemic. And there are other symptoms that can come along as well, but these are the four kind of cardinal features that we think about when we think about myeloma.

Once patients have these features, then you obviously have to intervene. Now clearly, the treatment or the approaches that we have taken for treatment of multiple myeloma has dramatically changed over the past 10, 15 years. A lot of those changes or primarily those changes have been because of (1) the new drugs that have come along; (2) our understanding of the biology of the disease. We have a better sense of which patients will not do as well as the next patient.

We also have significantly improved or supportive care. We can manage the infections better. We can manage the bone disease better because we have drugs like Aredia and Zometa. We can also provide better quality of life by managing the pain better. We can do procedures like kyphoplasty or vertebroplasty to deal with the vertebral fractures which can often be quite incapacitating in terms of pain.

So there is overall around improvement in how we deal with patients with multiple myeloma. As a starter, I think we will just going to focus on the actual therapy, the different treatments that we have available.

Jenny: Sure.

Dr. Kumar: So many of you who have dealt with myeloma and also have loved ones who have the disease. You would have heard about the names of some of the drugs we use in the clinic. The new ones that have been approved for treating myeloma over the past 10, 12 years include Velcade or bortezomib, which belongs to a class of drugs called proteasome inhibitors, then there is the thalidomide, Revlimid or lenalidomide, and pomalidomide or Pomalyst which all have been approved over the span of last 10 years or so and they all belong to a class of medications for immunomodulatory dug. But we know that these immunomodulation are altering the immune system is just one of the mechanisms under which these drugs act. So the multiple mechanism, all of which we still don’t understand fully about, but we all know well that this drug is so very effective in treating patients with myeloma.

Now what we have — the researchers in myeloma have done all these years is to try and see how best can we actually combine these new drugs either within the same group or I mean between the same group or in combination with the drugs that we had available for the past few decades, the old drugs which would be the cyclophosphamide, the melphalan, the doxorubicin, and drugs like that. So the series of trials Phase 1, Phase 2 trials, Phase 3 trials have looked at how best can we combine to come up with a regimen that is, one, very effective, which acts very rapidly and has very little in terms of side effects.

So there are several of those regimens that are currently being used, and I’m going to just take three examples of probably the most commonly used drugs. One of the things we use very commonly is the combination of lenalidomide or Revlimid and dexamethasone. Now, it’s convenient. It’s oral. It’s very well tolerated even in the older patients and it’s quite effective. We know that especially in patients who don’t have some of those high-risk features which I’ll come to you in a second, this combination of just lenalidomide and dexamethasone does very well.

Another combination is one where we have combined cyclophosphamide with Velcade or bortezomib and dexamethasone. That combination of three drugs is also very effective and we use that very often in patients who are going to stem cell transplant. We use that in patients who have high-risk multiple myeloma and again offers an option of an effective regimen. But in contrast with Revlimid and dexamethasone, the Velcade has to be given either intravenously or under the skin. Increasingly,we are using the Velcade under the skin once a week which ends up being a lot more convenient than how it used to be used in the past which was intravenously twice a week. Over the  years, we have found out that by using it once a week and using it subcutaneously, patients can tolerate this drug much better with very little neuropathy compared to when it’s given intravenously and twice weekly.

The third combination that is used very often is one where all these drugs are combined together. You have the Velcade, you have the Revlimid and then you have the dexamethasone. That combination of three drugs is very effective. It can be used in patients who have poor risk features multiple myeloma, and it produces a rapid response and seems to be fairly well tolerated. Those three probably are the most commonly used initial treatment that we use in this disease. Some of these patients might go into transplant and some may not and will come to the question of transplant in a second.

Before I go there, I want to highlight one of the change that has happened with this disease, that is this whole concept of how can we identify the patients who are unlikely to do as well as the others. The patients whom we call high risk multiple myeloma and these patients constitute about 15% to 25% of patients depending upon how we define these high-risk features. Now, why do we call them high-risk? The reason they call them high-risk is because we know that the survival of patients with these high-risk features tend to be considerably shorter compared to the rest of the patients.

So you are looking at about 20-25% of patients whose average survival is about years compared to 75% whose average survival is eight plus years. So there is clearly a group of patients who don’t do well. We really want to try and focus our attention on those patients because we think those patients clearly need some new treatment. We need to approach them differently and I think we have the maximum chance of showing a dramatic improvement in those patients by focusing our attention on those patients with new treatment.

Now, how do we identify these high-risk patients? The commonly used way is examining the bone marrow cells and the genetic makeup of those cells by using a test called FISH. Using FISH, we can look for particular markers or changes in the cells which will tell us that this particular patient is what we call a high-risk abnormality.

Another matter which is quite sensitive but it is not routinely used in the clinic is something called gene expression profiling. This is the most sophisticated test where they take these myeloma cells and look at how much a particular gene is active and they can survey a huge number of genes and give us a pattern so to speak. So it’s more of a pattern identification and we can look in at the pattern and say, “Okay this 15% of patients will do not as well as the remaining 85%.” That’s one of the test studies increasingly moving into the commercial space and maybe in a few years will be routinely available.

Jenny: That is through a bone marrow sample, right?

Dr. Kumar: Correct, right. So both of these things actually need those myeloma cells that come from the bone marrow so that they can do these tests on that. Now there are also lab tests that they can use to identify patients with high-risk and we can also do some test on the peripheral blood or the blood sample that is taken from the vein that also sometimes can give us some clues as to who has this high-risk features.

Now, why do we bother to look for these risk factors? Two reasons: one, if somebody has high-risk features we really want to make sure the patient is aware of that because they may be looking at very different approaches and maybe different outcomes. So I think it’s very important for patients to be informed. The second piece is I think we increasingly have started adapting a therapy based on what particular abnormality or what high-risk abnormality these patients have.

For example, if somebody has this high-risk abnormality what we call a loss of chromosome 17 or a part of the 17 chromosome is lost, those patients have often become resistant to treatment very fast and these patients are often approached differently. So for example a particular study was done in Germany recently where patients got Velcade-based treatments in the beginning and they got stem cell transplant and then they continued to get Velcade-based therapy off the transplant. In that trial, the patients with this particular high risk abnormality-based therapy off the transplant, in that trial the patients with these particular high-risk abnormality did the best that they have seen historically across multiple trials. Basically by knowing that particular abnormality exist, we can adapt a therapy for that particular patient.

Jenny: Oh, I think it’s wonderful.

Dr. Kumar: Yeah. So I think we are definitely getting-closer to personalizing treatment or individualizing treatment for patients with myeloma. There is no doubt there is a lot of work that needs to be done. What the studies looking into the genetic makeup of the cells gives us one very vital piece of information, and that is myeloma is not one disease. We call everything myeloma because they all — they have somewhat similar — the cells all so much similar to the bone marrow, but then you can break down the genetic makeup, we are probably dealing with a mix of five or six different diseases which all look similar, act somewhat similar but fundamentally are different depending upon what kind of genetic changes have happened in those cells and maybe in a few years, we will realize that these five or six different types or maybe more different types all have to have a recipe for managing them. But that’s clearly where we are headed with the advances that are happening in this disease.

Jenny: May I ask a question? What else needs to happen in order for that to happen now or in the next six months or a year?

Dr. Kumar: I think in the next six months or a year is probably going to be difficult because I think we really have to kind of peel off this layer by layer in trying to understand what are the changes. So we know it’s going to be very complicated because when one of the very first studies that we are done looking at sequencing basically reading the endogenetic framework of the myeloma cells. What they found was a huge number of genetic changes that happens in these myeloma cells.

But only the most common type of changes that they saw were only seen in three or four persons of these patients. Clearly now, we may have reached a stage where we are kind of dug way too deep in the sense that now we have a whole spectrum of changes, but we really want to identify a few changes that we can use to put these different myelomas into different blocks which in turn can tell us what different type of treatments can be used for them.

So I think that’s going to take a few years of work before that’s going to happen, but the good thing is the field is moving in that direction. We are increasingly starting to design clinical trials where we are not going to take everybody with myeloma but we are going to look for patients with a particular type of change and we are going to use a drug that we think can directly target that particular change in the myeloma cells. I think that the most important step is the realization and among the researchers that we are dealing with different diseases and we just cannot continue to rely on a one-size-fits-all approach and I think that is the key thing going forward in improving the outcomes.

Jenny: It would be fantastic if that would happen and I guess it would require some national or international studies if you narrowed it down to one type of patient like just a del 17 type of patient and wanted to treat them with adds some more complexities to clinical trials, I don’t know.

Dr. Kumar: It certainly does, I mean especially when you start looking at — myeloma is not a bad common disease. We are talking about 20,000 people a year in this country. Clearly, patients are living longer so you have a large number of patients living with the disease. But still when you start looking at smaller and smaller slice of the pie, we really need a lot of cooperation between different centers and as we said maybe even internationally to focus on these small, small groups of patients, but I think this definitely a move afoot to do that. There is a lot of collaboration between researchers and I think it’s going to happen. It’s not a matter of whether it’s going to happen, it’s a matter of when it’s going to happen and I think it’s going to be soon.

So I’m kind of moving back from that individualized approach until we get there. We still need to have new drugs that we can use to treat patients with myeloma. Of course, the unfortunate truth is that the vast majority of the patients with myeloma eventually do have the myeloma come back so we have to go back at it with something else, so that we can keep the disease under control for long periods of time.

What are the new things that are on the horizon? The way we look at it, there is — we can put them into kind of three different buckets. One, the drugs which look very similar to what we have in the clinic now, but they have some added advantages – either they can be taken by mouth instead of intravenously or they have a better side effect profile compared to what is currently being used. The second group are drugs which are a totally different class of drugs. They work very differently than any of the drugs we use currently and that I think is the most exciting part of everything that’s going on because we know that these myeloma cells eventually become resistant to what we can throw at them so we need some new tool which will work in a different way.

Finally, then this whole spectrum of different combinations that we are looking at of the old and the new drugs to see if they can actually make combinations that will work better than the sum of the two pieces, or three pieces that go into the combination. Let’s just look at the new drugs which are improved version of what we have right now. A good example of that would be the drug called MLN9708 or ixazomib. It’s an oral version of Velcade or bortezomib. It’s probably the easiest way to explain it. It is a pill that you take once a week and it’s very well absorbed. In the studies that we have done so far looking at the drug alone or in combination with the Revlimid and dexamethasone, again it’s difficult to compare different studies, but at least the ballpark area, I think it’s at least as active as the Velcade, but the advantage of these they can fill a week instead of having to go in and get an injection once a week.

The second thing is this drug seems to have a lot less neuropathy than Velcade has, so we may have managed to kind of negate two of the biggest drawbacks that Velcade have by using this drug. But clearly it is in clinical trials right now so we have to wait and see what happens and what the results are before it will become available in the clinic. There are two large trials ongoing. One is looking at the combination of MLN9708-Revlimid-dexamethasone in patients with relapsed myeloma and then there is a similar trial in patients with newly diagnosed myeloma.

We are also doing a couple of trials for this drug. One is in combination with cyclophosphamide and dexamethasone just like we did with Velcade in patients newly diagnosed with myeloma and then we are also looking at the drug in combination with dexamethasone in patients with relapsed disease. So these are the two trials that have not been done yet so we are in the process of actually enrolling patients for those trials and so far everything looks good.

Now, the other kind of me-too drug is the one which recently — the two ones that recently got approved. One is the carfilzomib that belongs to the same class of drugs as Velcade. It has been given intravenously. It has been given two days a week for three weeks and a week off, but clearly is a very effective drug and that’s why it got approved and it can be combined with some of the drugs we have in the clinic today and its combination with Revlimid and dexamethasone as it’s been shown in a trial that was done by Dr. Jackubowiak. It is again a very active combination. The question is how do these two very effective three-drug combinations — I mean where do we place them with respect to each of them and we don’t know the answer to that.

In order to answer that question, we are undertaking a large clinical trial with 756 patients with newly diagnosed myeloma that we are going to open up nationwide through the cooperative groups hopefully in the next two to three weeks. That will actually put half of the patients on the Velcade-Revlimid-dexamethasone and the other half of the patients on carfilzomib-Revlimid-dexamethasone. What you want to see is, is one better than the other in terms of how effective the drug is. Two is one drug better than or one combination better than the other in terms of how well patients can tolerate these medications. So we are very excited about having this trial open and we hope that we can put patients on this trial very fast and can answer a very important question.

Jenny: And I guess a next generation from that would be what about — you would then have to get through your phase 1 study of the MLN9708 and then it would be used kind of in a similar way in combination to see which one is better out of the three, right?

Dr. Kumar: Correct. And the question there is again may not be as much as efficacy as to whether the convenience and the quality of life aspects may be much better with one versus the other. So I think it’s an exciting time. You have new drugs coming along, we are doing all these clinical trials and I think it all benefits patients and as we have seen patients with myeloma living longer each year and it’s a steady progress that we have seen over the past decade.

Moving on to the drugs which are totally different class of drugs, I would say one of the most exciting drug that’s currently going through clinical trial are the antibodies. So what we call the monoclonal antibodies, these are antibodies directed against some protein that is present on the surface or these cancer cells. The best example of this success is the drug called rituximab that have changed the phase of lymphoma for example. We have for a long time have been yearning to get something similar to that in myeloma. And I think they are a lot closer to that. So there is this drug called elotuzumab that have already been shown to be quite active and you combine that with Revlimid and dexamethasone and there is a large phase three trial that completed enrollment and we are all eagerly waiting to see what the results would be.

The second antibody is something that was presented at the recent meeting, the ASCO meeting which is an anti-CD38 antibody. This again targets a different protein on the surface of myeloma cells. Based on the very limited results we see so far, it seems to be something that we need to be watching out for and hopefully we will have some results from those trials within the next couple of years.

Jenny: Can I ask you a question about CD38? How do you test for the presence of CD38? What kind of test do you use for that? Is that across all myeloma patients?

Dr. Kumar: So myeloma cells universally present have CD38 on the surface and that’s one of the ways we identify the myeloma cell. So we can look at that by two ways. One is we can take the bone marrow biopsy and stain them and look under the microscope or the more easy way to do is to take the liquid portion of the bone marrow and subject it to what we call a flow cytometry. What this machine does is you first kind of tag these myeloma cells with an antibody towards a CD38 and this antibody has kind of a color added to that antibody. When it goes through the machine, it can tell which cells have that antibody stuck to it which would be the ones which will have a CD38 present on the surface.

Jenny: Do all myeloma cells have CD38?

Dr. Kumar: Almost all myeloma cells have CD38 and they tend to be fairly rich in their expression. That’s why we think this antibody has quite a bit of promise in being quite selective in targeting the myeloma cells. So the antibody is clearly a very exciting area but there are other drugs that are being looked at to so we have a clinical trial that’s open looking at a drug called dinaciclib that — and I won’t go into the complicated details of the biology but suffice to say that it is a drug that we have seen in the lab being active against myeloma cells and most excitingly this drug actually can make myeloma cells become more sensitive to Velcade.

So we first did a trial on the dinaciclib alone and we saw that there is about 20% of these patients had the myeloma respond to treatment. So then we moved to the next phase where we are actually combining the dinaciclib with Velcade in one trial and combining the dinaciclib and carfilzomib in a second trial, both looking at patients with relapsed myeloma trying to see if we can actually replicate what we saw in the lab. That’s an exciting molecule.

Jenny: I understand that that one is being used in melanoma also, right? That drug or no? Do I have that wrong?

Dr. Kumar: The dinaciclib is being looked at both in chronic lymphocytic leukemia and that is the other main area that this drug is being examined right now. Then there is also another drug that the data has been presented and looks interesting is something called an Array-520. This is again is a drug that kind of driven the cell or disrupts the mechanism by this cell divides. So when the myeloma cells starts dividing, there are a kind of strands that form in the cells which allowed the chromosomes to be equally divided between the two daughter cells. What this drug does is poison the cell to the extended dose so the strands don’t form so the chromosomes cannot separate in an equal fashion and then the whole thing dies.

This drug is also currently being looked at and again about 20% to 30% of patients with myeloma, you can see a response to the treatment so they are also moving on to the next phase where this drug is being combined with either Velcade or carfilzomib to see if that combination would work better than the single drug. So those the two exciting drugs which are going through clinical trials. Now, there is a whole host of other drugs and I won’t go into all the details, but suffice to say that there is clearly a couple of dozen different drugs that are currently going through clinical trials at different centers across the country. And I think the future holds without a promise for being able to identify new therapies for treating myeloma.

Jenny: Okay. Just to back up for one second. Sometimes those are called immunotherapies, correct?

Dr. Kumar: That is correct. So I did not go into immunotherapy part of it. I kind of stopped with the antibody therapy, but that is also a very exciting feeling with all those new technology being developed where we can modify your T-cells and all those core cells that you have been hearing about. So manipulating the immune system is a new concept. It’s being going on for a long, long time, decades actually, but I think we are getting close to actually being successfully being able to do that. One of the best examples — for example the vaccine that was approved for treating prostate cancer, so that is one of the very first immunotherapy type approaches that have been approved. But now that we reach I think the tipping point for that one, I think we are going to start seeing a lot new immunotherapies that are going to come along as well.

Jenny: Okay, great. And then some of the other categories when you say new classes of drugs just so patients know because we see all things like HDAC inhibitors and CDK inhibitors and mTOR inhibitors and are very complicated.

Dr. Kumar: It is.

Jenny: Can you give us an idea of just basically what they do that are affecting cell production basically?

Dr. Kumar: So a majority of these drugs would interfere with the ability of the cell to divide or they might actually directly kill the cell. So many of these drugs or what you call targeted agents because they don’t just — they are not like it all cell poison like melphalan or cyclophosphamide, these tend to affect a specific what you call signaling pathways in the cells. So typically what happens in these myeloma cells or any cancer cell is that they may have some substance or chemical surrounding the cell that will bind to what we call a receptor on the cell surface and that receptor then sends some messages into the cell which then goes into the nucleus of the cell and then makes these genes active and make different proteins. So what many of these drugs do is kind of interfere or block that signaling process so it kind of chops off the communication lines between happens outside the cell and what happens inside the cell which then kind of stunts the cell and then cannot go any further or damages the cell to that extent that it just dies.

The mTOR inhibitors for example inhibits a pathway of what we call a PIK/AKT pathway. The CDK inhibitors inhibit what we call cyclin-dependent kinases which are enzymes which are involved in helping the cell move through the cell cycle of the division of the cell. And the HDAC inhibitor is something that interferes with the way that the genetic material uncoils or recoils which then in turn affects how well these genes can drive protein production. As we understand more and more about the critical biological aspects of these tumor cells, we can figure out ways of targeting what we think are the most important components of this biological process.

Jenny: Great.

Dr. Kumar: Now, one thing I didn’t talk about in much detail has been the role of stem cell transplantation in patients with myeloma. Now, the stem cell transplantation is something that’s been around for a long time. It’s very effective. It’s kind of giving a year’s medical treatment over in a couple of days. Basically, patients are getting high doses of chemotherapy which we hope will destroy most of the bad cells in their bone marrow, and then what we do is take the stem cells or the stem cells that have been collected before giving the chemotherapies and re-infused into this patient so that they can go into the bone marrow and start making new cells again.

So the bone marrow transplantation has been the autologous stem cell transplantation has been around for a while. It’s very effective. It still plays a very important role in the management of patients with myeloma, specifically patients who can undergo the stem cell transplant, the rigor of the stem cell transplant. It’s just like all the drugs. It’s the question of where do we use which approach not during the course of the disease. But we know is that you want to keep using — and it’s like a building blocks for the bridge that’s going to take us from an incurable disease to a curable disease.

If you have 65-year-old person whom we can keep using these drugs or approaches as one after the other and keep the person going until the person is 80 or 85, then you can say in essence that for that person that’s just been a cure because at 85, the likelihood is that the person might die of something else which is unrelated to myeloma. So depending upon what age you are talking about, the cure has a different connotation.

Jenny: Is there anything you’d like discuss or should we — because we have some callers with questions?

Dr. Kumar: We can certainly more into it. I think what I want to end with is a positive note and I think there are a lot of changes that are happening, all good changes, patients are living longer via more treatment options and we certainly are able to control the myeloma for a lot longer than what we have been able to do for a long time and I think that we are at a point where the discovery is accelerating over time and we are going to see new treatments come on faster and faster. So it’s a better time for patients with myeloma in terms of available treatment options.

Jenny: Oh, it seems like there is so much going on in myeloma. So it will be interesting to see how these early studies are working out. So a question about clinical trials before I open up to questions. From a patient’s perspective, if we participate in clinical trials, how much faster could we allow you to perform your work if a larger number of us were to participate?

Dr. Kumar: Jenny, I’m really so happy that you brought up this question because the clinical trials form, it’s basically the — it’s critically important for us to continue to make these advances that we have done in the past decade. To keep up the momentum, we have to be able to accrue patients to clinical trials. Unfortunately what’s happening is no more than 10% of patients with any cancer actually end up going on clinical trials

Now, there is a variety of different reasons. One, sometimes clinical trials can be very laborious. It involves patients having to come back to the clinic more often than otherwise we’d have to do. Sometimes, patients live far away from centers which have clinical trials available. So I think — but still I think the way we have to approach disease to one is obviously getting increased patient awareness. We are to make sure every patient knows that there are clinical trial options out there. We have to do a better education of patients in terms of how to find trials, how to look through them and how to help a health care professional actually explain to them what they can go on and what they cannot.

They can clearly go on to the website the www.clinicaltrial.gov and the myeloma foundation websites to find what trials are available for myeloma patients. They can always go to individual institution websites and find out lists of clinical trials available. For most of the institutions, I would say almost all of them, you can actually call somebody and they would be able to walk you through or at least go through the list and see if anything that would be an option for them. So I think overall, we need better patient education. We need better health care, provide education to make everyone realize how critical it is this whole clinical trial system for us to continue to make the progress that that we have made so far.

Jenny: I agree. That is why we are doing this just so we can help describe it I guess in an easy and understandable way. So when you go to the doctor, you have a little bit of knowledge with you and you can ask about their clinical trials. You can start being proactive about it.

Dr. Kumar: Absolutely.

Jenny: Okay. So we have several caller questions.

Caller: Hi. Thank you for taking my call. I have two questions. I will ask them both back to back and if you want to just take one or both, that would be great. My first question is for those patients who are in remission, are there any studies or clinical trials that aim to determine ways to increase the time in remission or maybe study those patients who manage to stay in remission for long periods of time maybe what are the some of the things that they are doing in order to achieve that. My second question is what is the role of donor transplant in treating multiple myeloma? Thank you.

Dr. Kumar: The first question, in terms of trying to — we have good drugs and good drug combinations which will help the vast majority of the patients to get into some form of remission, but we know that most — in almost all those patients, the myeloma will come back. So it — a lot of clinical trials are being done to look at the question, can we maintain those people in that response for longer than what we currently are able to do? These are some of the approaches, the two main approaches we are doing right now, one is called consolidation and one is called maintenance and sometimes is very hard to make out the difference between the two and it is kind of a grey, fuzzy zone in between.

Essentially all of them boil down to once you get to that remission can we give some additional treatments either intense treatment for a short period of time or very light treatment over extended period of time to try and keep pushing those cells down, keep a lid on those myeloma cells so that the myeloma does not come back for a long period of time. Now, the biggest problem is that two scenarios: One, we could actually not treat and let the myeloma come back and use the drug at that time to treat the disease or we could keep somebody on the drug a long period of time knowing that the myeloma is going to come back late. But when it does come back, we will have one drug less that we have available to treat the disease.

So what we really want to prove is by intervening kind of early before the relapse happens and by keeping people on a lower dose for a long period of time, we can actually not only just prevent the myeloma from coming back late, we can actually make people live longer. That means we want to change the fundamental — keep the biology of the disease by keeping up the treatment for a long period of time. That’s kind of why the clinical trials are looking at more of these maintenance approaches and the consolidation approaches.

Whether any of them would be better than what we do right now still remains controversial because, for example, in the post-transplant setting, there were two trials that were done looking at Revlimid with maintenance. One showed that people are living longer and the one that was done in France has not shown any benefit in terms of people living longer. So the jury is still out on that one.

The second question regarding the donor transplant or allogeneic stem cell transplant, now this is a modality that has been used in a variety of different hematological cancers especially leukemia. The fundamental concept is different than autologous stem cell transplant which is essentially relying on a very high dose of chemotherapy to kill the cells. And the stem cells are given back just for the purpose of kind of repopulating or re-seeding the bone marrow. In contrast, in the allogeneic stem cell transplant, what we are hoping to do is get some foreign cells into the system and allow them to live in that system, meaning the patient’s body, and have these new cells recognize the tumor as a foreign cell and destroy the tumor cells, but at the same time do not wreak too much of a havoc to the normal cells.

The allogeneic transplant have a lot of trials being done again. None of the trials have shown that the allogeneic transplant is any better than the autologous stem cell transplant, but I think the biggest problem has been we have really not asked the correct question which is realizing that the allogeneic transplant is a more dangerous procedure with more side effects. What we really need to do is to look at the patients in whom the current treatments don’t work well at all, like the really risk patients and seeing if those patients can use the allogeneic stem cell transplant to make a difference. I think some of those trials are ongoing at this point as well. So I think it’s certainly a valuable approach but I would suggest that it always needs to be done in the context of a clinical trial as much as possible

Jenny: Thank you so much for your question and thank you so much for the excellent answers. Okay. We have another caller question.

Caller: Hi, Dr, Kumar and Jenny.

Jenny: You are on.

Dr. Kumar: Hello.

Caller:  All right. Greetings from New York.

Dr. Kumar: Greetings.

Caller:  Yeah. Thank you for the service that both of you are doing, Jenny for the show and for your tireless effort and turning up great interviews and Dr. Kumar for the great work you are doing. I have a question for you Dr. Kumar. What do you see on the horizon? Do you see any major disruptions on the horizon happening in myeloma? Is there anything that you haven’t discussed that I’m not — I’m just saying go out there and stretch a little bit. What’s next? Something that may not be mainstream.

Dr. Kumar: Right. So I think the next — because revolution I think is going to be the individual x medicine understanding the genetic abnormality and going after that with specific drugs. It’s really hard to know how much that’s going to impact at this point because you are still kind of searching for those targets, but the key thing is that any mutational chains that’s being described in the cancer cells, the whole machinery to develop a molecule to attack the target is kind of very well in place. So the key is identifying what are the changes that drive the myeloma cells? Once we know that it’s a very easy thing to develop drugs that will target that. It’s I think the search for the Achilles heel is basically what is going to be the most rewarding over the next few years I think.

Caller: Okay. That’s really where you think the next innovation is going to happen? Who is working on stuff like that?

Dr. Kumar: So I think the search is all around the country and also in a lot of Europe are also looking in that. I think what is made possibly is you can literally seek to hold genome in the myeloma cells for a lot lower than what we could do before. So I think some of the studies — once we have a huge number of patients studied in that manner, then you will be able to do a better analysis of these genetic changes to see how commonly they happen, and then we kind of go after what is the most common ones and it’s going to be an iterative process that you might not strike gold all the time, but at least a few of them are going to pan out and it’s just a matter of eventually identifying changes that would account for all the myeloma.

Caller: I was thinking of having my genome sequenced. I found that I could do it for about $2,000 right now which is unbelievable and they say that next year is going to be a $1,000 and about a few years down the road will be $100.

Dr. Kumar: It’s getting cheaper at the rate that which all the computer processors are getting faster.

Caller: I think it’s actually a beating computer processing. It’s going down faster than that. Have any of your patients sequence the genome and this — if I were to go out and sequence my genome right now, would that be it? Is anybody that would — would they just look at me strange and cross-eyed or is there anybody that could do anything with it?

Dr. Kumar: I’m sure you will get a few strange looks. There is no doubt about it. But the question is whether we can actually do anything about it. I think that is going to be the next step because you might sequence the genome and will say that we came here about  60 different mutations that you are going to find them that myeloma cell. Now, which one would we go after? That’s something you won’t be able to know for sure, but in case let’s say we had a 1,000 people with genomes have been looked at and we find the same mutation in let’s say 30 of them, then we feel more confident going after that.

Caller: That would help you to buy myself it’s not that big a deal, but if maybe a thousand people did it, it would generate some targets for the researchers to go after then we can just open source that data to make it available to the researchers maybe.

Dr. Kumar: But then it comes back to you in the sense that let’s say if you are one of the thousand and you have 50 mutations and one of them we know happens in 50 out of the 1,000 and that’s the one people are going to after for you as well.

Caller: This puts up an interesting question around privacy. Before I used to care about privacy, but now I don’t. I think anybody who has got a disease if it’s cancer, they don’t care about privacy anymore. They are like, “Just cure me, darn it.” So I wonder if people would be willing to just open up their data and just say, “Here cure me.” Anyways, so thanks for taking the question. I don’t want to hog the time but keep up the great work.

Dr. Kumar: Thank you.

Jenny: Okay. Yeah. Thank you so much for your question. Okay. We have one more caller question.

Caller: Yes. Doctor, thank you so much for your time today. My question is what should a patient ask about their test to arm themselves with enough information to work towards targeted therapies?

Dr. Kumar: Sorry. I missed that. What kind of information does the patient need to —

Caller: Yeah. What should I ask about my test so that I got the information I need so that I can go and get a more targeted therapy.

Dr. Kumar: What kind of targeted therapy you can get is kind of limited by what is out there in the clinical trials right now. For example, if you have a particular let’s say genetic change identifying cell ,which we have seen in other types of cancers and maybe there is a drug that’s approved for that. Your physician may be able to try something which is off-label kind of a thing, but that is not the way we want to approach this. We want to do that in a systematic fashion so that we do all these things in the context of clinical trials. So I think the basic information that I think will help us today is like the FISH testing, the cytogenetic testing that we can act upon today. Things like sequencing or the genome testing is something that the amount of information has to get to a tipping point before we can actually do anything about it. But again, it depends on the clinical trials at this point.

Caller: But as a lay patient, are there parts of that test that I should focus on so that I can be more informed myself as them reviewing these options with the doctors?

Dr. Kumar: I think the genomic information of the same is probably not prime time for you to take to a physician and say, “Okay, I have this mutation. What can you do for me?” I think that has to be done in the context of clinical trials. But the other information the FISH studies, somebody that the newly diagnosed myeloma I think it’s important that they get a FISH testing done on the bone marrow. So we had that piece of information would be critical so that they can insist that happens.

Caller: Okay. I really appreciate you taking your time with us today. Thank you very much.

Dr. Kumar: You’re welcome.

Jenny: Thank you for your call. Well, Dr. Kumar, we are going to close because our time is up. Thank you so much for joining us today.

Dr. Kumar: Thank you, Jenny for doing this.

Jenny: Well, thank you for all that you are doing to move forward towards the cure for myeloma and better outcomes for all myeloma patients. We are just really very grateful.

Dr. Kumar: All the best to everyone who has been listening and thank you. Bye.

Jenny: Thank you so much.

Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient radio interview as we learn more about how we can help drive to a cure for myeloma.

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